Human Molecular Genetics Advance Access originally published online on July 27, 2005
Human Molecular Genetics 2005 14(17):2491-2500; doi:10.1093/hmg/ddi250
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sacred disease secrets revealed: the genetics of human epilepsy
1Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8, 2Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618, USA, 3Center for the Study of Brain Diseases, Centre Hospitalier de l'Université de Montréal, Notre Dame Hospital, Montreal, Quebec, Canada H2L 4M1 and 4Epilepsy Center of Excellence, Greater Los Angeles VA Healthcare System, Los Angeles, CA 90073, USA
* To whom correspondence should be addressed at: Program in Genetics and Genomic Biology and Department of Paediatrics (Neurology), The Hospital for Sick Children, Toronto, Canada M5G 1X8. Tel: +1 4168136291; Fax: +1 4168136334; Email: bminass{at}sickkids.ca
Received June 15, 2005; Accepted July 8, 2005
Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the ‘sacred’ disease. Genes underlying the ‘malevolent’ forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. A. Patino, L. R. F. Claes, L. F. Lopez-Santiago, E. A. Slat, R. S. R. Dondeti, C. Chen, H. A. O'Malley, C. B. B. Gray, H. Miyazaki, N. Nukina, et al. A Functional Null Mutation of SCN1B in a Patient with Dravet Syndrome J. Neurosci., August 26, 2009; 29(34): 10764 - 10778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Addabbo, M. Montagnani, and M. S. Goligorsky Mitochondria and Reactive Oxygen Species Hypertension, June 1, 2009; 53(6): 885 - 892. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Khosravani and G. W. Zamponi Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev, July 1, 2006; 86(3): 941 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.D. Graves Ion channels and epilepsy QJM, April 1, 2006; 99(4): 201 - 217. [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Kearney, Y. Yang, B. Beyer, S. K. Bergren, L. Claes, P. DeJonghe, and W. N. Frankel Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2 Hum. Mol. Genet., March 15, 2006; 15(6): 1043 - 1048. [Abstract] [Full Text] [PDF]
|
|